Injured Purkinje Cells Implicated in Preemies' Locomotor Learning Deficits

By Marilynn Larkin

March 19, 2021

NEW YORK (Reuters Health) - Injury to Purkinje cells during fetal and early postnatal life is likely responsible for locomotor learning deficits in very premature infants, researchers say.

"Using an animal model of neonatal brain injury that captures the major hallmarks of the injury seen in human newborns, our work uncovers how injury during this early period affects the function of neurons that control adaptive or anticipatory movement, namely the Purkinje cells," Dr. Aaron Sathyanesan of Children's National Hospital in Washington, DC told Reuters Health by email.

"The main technical advance in our paper is that we devised a method to monitor the activity of Purkinje cells in animals that were performing a locomotor learning task," he said.

"Since our animal model aims to mimic injury in human newborns, which is often a brain-wide injury, we wanted to know how specific the behavioral changes were to alterations in Purkinje cell function during the early neonatal period," he explained.

"We used a method to artificially silence Purkinje cell firing during the neonatal period in mice that were not exposed to the injury paradigm," he continued. "The results were quite striking. Both the long-term behavioral measurement and the physiological responses of the Purkinje cells during learning were quite similar to what we observed in animals that were exposed to the injury paradigm."

"This indicates that Purkinje cell activity during the neonatal period is critical for normal behavior in the long-term," he concluded.

Specifically, the researchers measured neural circuit function in the mouse model by pairing GcaMP6f fiber photometry, which measures neuronal activity during movement, with an Erasmus Ladder, which tests motor learning and performance. They introduced obstacles to movement and observed how quickly the mice learned to avoid the obstacle, according to the study published in Proceedings of the National Academy of Sciences of the USA.

A series of learning trials plus brain monitoring comparing brain-injured and normal animal models enabled the team to quantify cerebellum-dependent locomotor learning and adaptive behavior. Further, as Dr. Sathyanesan noted, they found that Purkinje cell dysfunction in the brain-injured model specifically interfered with adapted learning, and that switching these cells off (chemogenetic inhibition) in normal models mimicked the effects of perinatal cerebellar injury.

The authors state, "Our results uncover a direct link between perinatal cerebellar injury and activity-dependent maturation of cerebellar cortex."

Dr. Sathyanesan said, "Broadly speaking, the take-home message for clinicians and drug development companies is to pay attention to neurodevelopmental processes, including the formation of neural circuits that may be altered due to neonatal brain injury. These neurobiological systems can be quite different during development compared to those of a mature adult, including the kinds of receptors that are present in neurons and other cells in the brain."

Dr. David Hackam, Pediatric Surgeon-in-Chief and Co-Director, Johns Hopkins Children's Center in Baltimore, commented in an email to Reuters Health, "This work highlights the importance of understanding the early events that lead to neurological dysfunction in neonates, and provides additional evidence that early injury can have lasting impact."

"One of the most striking aspects of the work is the observation that a relatively understudied population of cells, namely Purkinje cells, can have such profound effects on long-term neurological function," he noted. "The study also presents very novel techniques for the selective reduction of Purkinje cell function early in life."

"This study opens the door for assessing whether these pathways are also active in infants with neurological dysfunction, and then to perhaps developing specific neuroprotective strategies by targeting Purkinje cells in the neonatal brain," Dr. Hackam concluded.

SOURCE: https://bit.ly/30YoQpP Proceedings of the National Academy of Sciences of the USA, online March 16, 2021.

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